Khan et al. demonstrate that the lower female reproductive tract is exceptionally vulnerable to infection by LCMV and Zika virus, as intravaginal exposure to these RNA viral pathogens elicits a dampened antiviral immune response.

Parameters required for eliciting CD8-T-cell-mediated immunity in the tolerogenic environment of female reproductive tract (FRT) are not well understood. We established a mouse model of intravaginal infection with acute lymphocytic choriomeningitis virus (LCMV) and showed that, compared to systemic infection, CD8-T-cell-mediated protective immune response was delayed in the FRT. After i.vag. LCMV infection, live virus is transmitted to the draining iliac lymph node (iLN) from the lower female reproductive tract (LFRT), which helps to prime virus-specific CD8 T cells in the iLN and restricts further systemic spread of the virus. However, T-cell priming in the iLN of i.vag. mice is delayed compared to that in i.p. infected mice, causing a delay in the appearance of effector CD8 T cells in the LFRT. This delayed CD8 T-cell response in LFRT provides LCMV a window of opportunity to replicate robustly in this immune privileged site. Mechanistically, the delay in CD8 T-cell priming is due to suboptimal activation of LFRT migratory DCs, which require further maturation upon migration into the iLN. As a potential cause of the suboptimal DC activation, we found that LFRT expresses limited steady-state levels of viral RNA-sensing pattern-recognition-receptors and elicits minimal induction of interferons and other inflammatory mediators required for anti-viral immunity. These findings provide a mechanistic explanation for the cause of the delay in CD8 T-cell activation after intravaginal viral infection and emphasize the notion that successful vaccination against RNA viruses may require adjuvants that elicit a stronger innate immune response than that provided by live viruses.